1. Field of the Invention
The invention concerns a new approach for the management of immune diseases using novel fusion polypeptides. More specifically, the invention is related to the treatment of immune diseases, where management of the disease comprises suppressing an inappropriate or unwanted immune response, such as, for example, autoimmune diseases and allergic diseases.
2. Description of the Related Art
Immunoglobulin Receptors
Immunoglobulin receptors (also referred to as Fc receptors) are cell-surface receptors binding the constant region of immunoglobulins, and mediate various immunoglobulin functions other than antigen binding.
Fc receptors for IgE molecules are found on many cell types of the immune system (Fridman, W., FASEB J., 5(12):2684-90 (1991)). There are two different receptors currently known for IgE. IgE mediates its biological responses as an antibody through the multichain high-affinity receptor, FcεRI, and the low-affinity receptor, FcεRII. The high-affinity FcεRI, expressed on the surface of mast cells, basophils, and Langerhans cells, belongs to the immunoglobulin gene superfamily, and has a tetrameric structure composed of an α-chain, a β-chain and two disulfide-linked γ-chains (Adamczewski, M., and Kinet, J. P., Chemical Immun., 59:173-190 (1994)) that are required for receptor expression and signal transduction (Tunon de Lara, Rev. Mal. Respir., 13(1):27-36 (1996)). The α-chain of the receptor interacts with the distal portion of the third constant domain of the IgE heavy chain. The specific amino acids of human IgE involved in binding to human FcεRI have been identified as including Arg-408, Ser-411, Lys-415, Glu-452, Arg-465, and Met-469 (Presta et al., J. Biol. Chem. 269:26368-73 (1994)). The interaction is highly specific with a binding constant of about 1010M−1.
The low-affinity FcεRII receptor, represented on the surface of inflammatory cells, including eosinophils, leukocytes, B lymphocytes, and platelets, did not evolve from the immunoglobulin superfamily but has substantial homology with several animal lectins (Yodoi et al., Ciba Found. Symp., 147:133-148 (1989)) and is made up of a transmembrane chain with an intracytoplasmic NH2 terminus. The low-affinity receptor, FcεRII (CD23) is currently known to have two forms (FcεRIIa and FcεRIIb), both of which have been cloned and sequenced. They differ only in the N-terminal cytoplasmic region, the extracellular domains being identical. FcεRIIa is normally expressed on B cells, while FcεRIIb is expressed on T cells, B cells, monocytes and eosinophils upon induction by the cytokine IL-4.
Through the high-affinity IgE receptor, FcεRI, IgE plays key roles in an array of acute and chronic allergic reactions, including asthma, allergic rhinitis, atopic dermatitis, severe food allergies, chronic urticaria and angioedema, as well as the serious physiological condition of anaphylactic shock as results, for example, from bee stings or penicillin allergy. Binding of a multivalent antigen (allergen) to antigen-specific IgE specifically bound to FcεRI on the surface of mast cells and basophils stimulates a complex series of signaling events that culminate in the release of host vasoactive and proinflammatory mediators contributing to both acute and late-phase allergic responses (Metcalfe et al., Physiol. Rev. 77:1033-1079 (1997)).
The function of the low affinity IgE receptor, FcεRII (also referred to as CD23), found on the surface of B lymphocytes, is much less well established than that of FcεRI. FcεRII, in a polymeric state, binds IgE, and this binding may play a role in controlling the type (class) of antibody produced by B cells.
Three groups of receptors that bind the constant region of human IgG have so far been identified on cell surfaces: FcεRI (CD64), FcγRII (CD32), and FcγRIII (CD16), all of which belong to the immunoglobulin gene superfamily. The three Fcγ receptors have a large number of various isoforms.
Along with the stimulatory FcεRI, mast cells and basophils co-express an immunoreceptor tyrosine-based inhibition motif (ITIM)-containing inhibitory low-affinity receptor, FcγRIIb, that acts as a negative regulator of antibody function. FcγRIIb represents a growing family of structurally and functionally similar inhibitory receptors, the inhibitory receptor superfamily (IRS), that negatively regulate immunoreceptor tyrosine-based activation motif (ITAM)-containing immune receptors (Ott and Cambier, J. Allergy Clin. Immunol., 106:429-440 (2000)) and a diverse array of cellular responses. Coaggregation of an IRS member with an activating receptor leads to phosphorylation of the characteristic ITIM tyrosine and subsequent recruitment of the SH2 domain-containing protein tyrosine phosphatases, SHP-1 and SHP-2, and the SH2 domain-containing phospholipases, SHIP and SHIP2 (Cambier, J. C., Proc. Nat. Acad. Sci. USA, 94:5993-5995 (1997)). Possible outcomes of the coaggregation include inhibition of cellular activation, as demonstrated by the coaggregation of FcγRIIb and B-cell receptors, T-cell receptors, activating receptors, including FcεRI, or cytokine receptors (Malbec et al., Curr. Top. Microbiol. Immunol., 244:13-27 (1999)).
Most studies have so far concentrated on elucidating the mechanisms of FcγRII, in particular, FcγRIIb function. The three alternatively spliced isoforms of the FcγIIb receptor, of which FcγRIIb1 is only found in mice, and FcγRIIb1 and FcγRIIb2 are expressed in both humans and mice, have Ig-like loops and a conserved ITIM, but differ in their cytoplasmic domains. Co-crosslinking of the high-affinity FcεRI receptor and the inhibitory low-affinity receptor FcγRII blocks a number of processes, including FcεRI-mediated secretion, IL-4 production, Ca2+ mobilization, Syk phosphorylation, and FcεRI-mediated basophil and mast cell activation. In B cells, co-crosslinking of the B-cell receptor and FcγRIIb inhibits B-cell receptor-mediated cell activation (Cambier, J. C., Proc. Natl. Acad. Sci., 94:5993-5995 (1997); Daeron, M., Annu. Rev. Immunol, 15:203-234 (1997)), and specifically, inhibits B-cell receptor-induced blastogenesis and proliferation (Chan et al., Immunology, 21:967-981 (1971); Phillips and Parker, J. Immunol., 132:627-632 (1984)) and stimulates apoptosis (Ashman et al., J. Immunol, 157:5-11 (1996)). Coaggregation of FcγRIIb1 or FcγRIIb2 with FcγRI in rat basophilic leukemia cells, inhibits FcεRI-mediated release of serotonin and TNF-α (Daeron et al., J. Clin. Invest., 95:577-85 (1995); Daeron et al., Immunity, 3:635-646 (1995)).
Another ITIM-containing receptor expressed on mast cells that has been described to prevent IgE-mediated mast cell activation when coligated with FcεRI, is a 49 kDa glycoprotein member of the immunoglobulin superfamily, termed gp49b1 (gp91) (see, e.g., Wagtmann et al., Current Top. Micobiol. Immunol. 244:107-113 (1999); Katz, H. R., Int. Arch Allergy Immunol. 118:177-179 (1999); and Lu-Kuo et al., J. Biol. Chem. 274:5791-96 (1999)). Gp49b1 was originally identified in mice, while human counterparts of the gp49 family, including gp49b1, have been cloned by Arm et al., J. Immunol. 15:2342-2349 (1997). Further ITIM-containing receptors, several expressed in mast cells, basophils or B cells are reviewed by Sinclair N R, Scand. J. Immunol., 50:10-13 (1999).
Through the high-affinity IgE receptor FcεRI, IgE plays key roles in immune response. The activation of mast cells and basophils by antigen (i.e., allergen) via an antigen-specific IgE/FcεRI pathway results in the release of host vasoactive and proinflammatory mediators (i.e., degranulation), which contributes to the allergic response (Oliver et al., Immunopharmacology 48:269-281 [2000]; Metcalfe et al., Physiol. Rev., 77:1033-1079 [1997]). These and other biochemical events lead to the rapid secretion of inflammatory mediators such as histamine, resulting in physiological responses that include localized tissue inflammation, vasodilation, increased blood vessel and mucosal permeability, and local recruitment of other immune system cells, including additional basophils and mast cells. In moderation, these responses have a beneficial role in immunity against parasites and other microorganisms. However, when in excess, this physiological response results in the varied pathological conditions of allergy, also known as type I hypersensitivity.
Allergic Conditions
Allergy is manifested in a broad array of conditions and associated symptoms, which may be mild, chronic, acute and/or life threatening. These various pathologies include, for example, allergic asthma, allergic rhinitis, atopic dermatitis, severe food allergies, chronic urticaria and angioedema, as well as the serious physiological condition of anaphylactic shock. A wide variety of antigens are known to act as allergens, and exposure to these allergens results in the allergic pathology. Common allergens include, but are not limited to, bee stings, penicillin, various food allergies, pollens, animal detritus (especially house dust mite, cat, dog and cockroach), and fungal allergens. The most severe responses to allergens can result in airway constriction and anaphylactic shock, both of which are potentially fatal conditions. Despite advances in understanding the cellular and molecular mechanisms that control allergic responses and improved therapies, the incidence of allergic diseases, especially allergic asthma, has increased dramatically in recent years in both developed and developing countries (Beasley et al., J. Allergy Clin. Immunol. 105:466-472 (2000); Peat and Li, J. Allergy Clin. Immunol. 103:1-10 (1999)). Thus, there exists a strong need to develop treatments for allergic diseases.
Allergic asthma is a condition brought about by exposure to ubiquitous, environmental allergens, resulting in an inflammatory response and constriction of the upper airway in hypersensitive individuals. Mild asthma can usually be controlled in most patients by relatively low doses of inhaled corticosteroids, while moderate asthma is usually managed by the additional administration of inhaled long-acting β-antagonists or leukotriene inhibitors. The treatment of severe asthma is still a serious medical problem. In addition, many of the therapeutics currently used in allergy treatment have serious side-effects. Although an anti-IgE antibody currently in clinical trials (rhuMAb-E25, Genentech, Inc.) and other experimental therapies (e.g., antagonists of IL-4) show promising results, there is need for the development of additional therapeutic strategies and agents to control allergic disease, such as asthma, severe food allergy, and chronic urticaria and angioedema.
One approach to the treatment of allergic diseases is by use of allergen-based immunotherapy. This methodology uses whole antigens as “allergy vaccines” and is now appreciated to induce a state of relative allergic tolerance. This technique for the treatment of allergy is frequently termed “desensitization” or “hyposensitization” therapy. In this technique, increasing doses of allergen are administered, typically by injection, to a subject over an extended period of time, frequently months or years. The mechanism of action of this therapy is thought to involve induction of IgG inhibitory antibodies, suppression of mast cell/basophil reactivity, suppression of T-cell responses, the promotion of T-cell anergy, and/or clonal deletion, and in the long term, decrease in the levels of allergen specific IgE. The use of this approach is, however, hindered in many instances by poor efficacy and serious side-effects, including the risk of triggering a systemic and potentially fatal anaphylactic response, where the clinical administration of the allergen induces the severe allergic response it seeks to suppress (TePas et al., Curr. Opin. Pediatrics 12:574-578 [2000]).
Refinements of this technique use smaller portions of the allergen molecule, where the small portions (i.e., peptides) presumably contain the immunodominant epitope(s) for T cells regulating the allergic reaction. Immunotolerance therapy using these allergenic portions is also termed peptide therapy, in which increasing doses of allergenic peptide are administered, typically by injection, to a subject. The mechanism of action of this therapy is thought to involve suppression of T-cell responses, the promotion of T-cell anergy, and/or clonal deletion. Since the peptides are designed to bind only to T cells and not to allergic (IgE) antibodies, it was hoped that the use of this approach would not induce allergic reactions to the treatment. Unfortunately, these peptide therapy trials have met with disappointment, and allergic reactions are often observed in response to the treatments. Development of these peptide therapy methods have largely been discontinued.
Autoimmune Diseases
It is estimated that as much as 20 percent of the American population has some type of autoimmune disease. Autoimmune diseases demonstrate disproportionate expression in women, where it is estimated that as many as 75% of those affected with autoimmune disorders are women. Although some forms of autoimmune diseases are individually rare, some diseases, such as rheumatoid arthritis and autoimmune thyroiditis, account for significant morbidity in the population (Rose and MacKay (Eds.), The Autoimmune Diseases, Third Edition, Academic Press [1998]).
Autoimmune disease results from failure of the body to eliminate self-reactive T-cells and B-cells from the immune repertoire, resulting in circulating B-cell products (i.e., autoreactive antibodies) and T-cells that are capable of identifying and inducing an immune response to molecules native to the subject's own physiology. Particular autoimmune disorders can be generally classified as organ-specific (i.e., cell-type specific) or systemic (i.e., non-organ specific), but with some diseases showing aspects of both ends of this continuum. Organ-specific disorders include, for example, Hashimoto's thyroiditis (thyroid gland) and insulin dependent diabetes mellitus (pancreas). Examples of systemic disorders include rheumatoid arthritis and systemic lupus erythematosus. Since an autoimmune response can potentially be generated against any organ or tissue in the body, the autoimmune diseases display a legion of signs and symptoms. Furthermore, when blood vessels are a target of the autoimmune attack as in the autoimmune vasculitides, all organs may be involved. Autoimmune diseases display a wide variety of severity varying from mild to life-threatening, and from acute to chronic, and relapsing (Rose and MacKay (Eds.), The Autoimmune Diseases, Third Edition, Academic Press [1998]; and Davidson and Diamond, N. Engl. J. Med., 345(5):340-350 [2001]).
The molecular identity of some of the self-reactive antigens (i.e., the autoantigen) are known in some, but not all, autoimmune diseases. The diagnosis and study of autoimmune diseases is complicated by the promiscuous nature of these disorders, where a patient with an autoimmune disease can have multiple types of autoreactive antibodies, and vice versa, a single type of autoreactive antibody is sometimes observed in multiple autoimmune disease states (Nocci et al., Curr. Opin. Immunol., 12:725-730 [2000]; and Davidson and Diamond, N. Engl. J. Med., 345(5):340-350 [2001]). Furthermore, autoreactive antibodies or T-cells may be present in an individual, but that individual will not show any indication of disease or other pathology. Thus while the molecular identity of many autoantigens is known, the exact pathogenic role of these autoantigens generally remains obscure (with notable exceptions, for example, myesthenia gravis, autoimmune thyroid disease, multiple sclerosis and diabetes mellitus).
Treatments for autoimmune diseases exist, but each method has its own particular drawbacks. Existing treatments for autoimmune disorders can be generally placed in two groups. First, and of most immediate importance, are treatments to compensate for a physiological deficiency, typically by the replacement of a hormone or other product that is absent in the patient. For example, autoimmune diabetes mellitus can be treated by the administration of insulin, while autoimmune thyroid disease is treated by giving thyroid hormone. Treatments of other disorders entails the replacement of various blood components, such as platelets in immune thrombocytopenia or use of drugs (e.g., erythropoetin) to stimulate the production of red blood cells in immune based anemia. In some cases, tissue grafts or mechanical substitutes offer possible treatment options, such as in lupus nephritis and chronic rheumatoid arthritis. Unfortunately, these types of treatments are suboptimal, as they merely alleviate the disease symptoms, and do not correct the underlying autoimmune pathology and the development of various disease related complications. Since the underlying autoimmune activity is still present, affected tissues, tissue grafts, or replacement proteins are likely to succumb to the same immune degeneration.
The second category of autoimmune disease treatments are those therapies that result in generalized suppression of the inflammatory and immune response. This approach is difficult at best, as it necessitates a balance between suppressing the disease-causing immune reaction, yet preserving the body's ability to fight infection. The drugs most commonly used in conventional anti-inflammatory therapy to treat autoimmune disorders are the non-steroidal anti-inflammatory drugs (e.g., aspirin, ibuprofen, etc). Unfortunately, these drugs simply relieve the inflammation and associated pain and other symptoms, but do not modify progression of the disease. Broad acting immunosuppressants, such as cyclosporine A, azathioprine, cyclophosphamide, and methotrexate, are commonly used to treat symptoms as well as hopefully ameliorate the course of the autoimmune process. Although somewhat successful in controlling the autoimmune tissue injury, these broad acting and powerful drugs often have severe side effects, such as the development of neoplasias, destruction of bone marrow and other rapidly dividing cells and tissues, and risk of liver and kidney injury. Furthermore, these drugs have the undesirable consequence of depressing the patient's immune system, which carries the risk of severe infectious complications. For these reasons, general suppression of the immune system is generally reserved for the treatment of severe autoimmune disorders, such as dermatomyositis and systemic lupus erythematosus (SLE) or when there is involvement of a critical organ, such as the heart.
More preferably, successful immuno-suppressive therapies for autoimmune disorders will suppress the immune system in an autoantigen-specific manner (i.e., antigen-restricted tolerance), similar to that proposed for allergen immunotolerance therapy to induce desensitization (Harrison and Hafler, Curr. Opin. Immunol., 12:704-711 [2000]; Weiner, Annu. Rev. Med., 48:341-351 [1997]; and Mocci et al., Curr. Opin. Immunol., 12:725-730 [2000]). Refinements of this approach have used smaller portions of the autoantigen (i.e., autoantigenic peptides) which contain the immunodominant epitope(s), using oral and parenteral administration protocols. Like allergy peptide therapies, administration of autoantigen peptides is now recognized to be accompanied by significant risk of allergic/hypersensitivity reactions and potentially fatal anaphylactic response. These risks also limit the amount of peptide that can be administered in a single dose. For these and other reasons, peptide immunotolerance therapies for the treatment of autoimmune diseases in humans have been problematic, and many have failed to find widespread applicability. These tolerance therapies remain largely unusable, unless the risk of allergic reactions can be overcome.
Autoimmune type-I diabetes mellitus is a form of insulin-dependent diabetes resulting from immune recognition of insulin or those cells that produce insulin, i.e., the pancreatic islet β-cells, leading to immune-mediated destruction of the β-cells, and reduction of insulin production or activity. The disease is thought to be initiated by multiple etiologies, but all resulting in insulin deficiency. The known autoantigen targets of autoimmune diabetes include insulin and glutamic acid decarboxylase (GAD) (Chaillous et al., Diabetologia 37(5):491-499 [1994]; Naquet et al., J. Immunol., 140(8):2569-2578 [1988]; Yoon et al., Science 284(5417):1183-1187 [1999]; Nepom et al., Proc. Natl. Acad. Sci. USA 98(4):1763-1768 [2001]). In addition to insulin and GAD, additional β-cell autoantigens are theorized to exist (Nepom, Curr. Opin. Immunol., 7(6):825-830 [1995]).
Tolerance therapies incorporating either parenterally and orally administered diabetes autoantigens (including insulin and GAD) have been tried in experimental models and human subjects. However, the majority of human trials have met with disappointment. Furthermore, widespread application of peptide therapy in humans to treat autoimmune diabetes has been prevented by the observation that in some cases, peptide administration may actually accelerate disease progression (Pozzilli et al., Diabetologia 43:1000-1004 [2000]; Gale, Lancet 356(9229):526-527 [2000]; Chaillous et al., Lancet 356:545-549 [2000]; Blanas et al., Science 274:1707-1709 [1996]; McFarland, Science 274(5295):2037 [1996]; and Bellmann et al., Diabetologia 41:844-887 [1998]).
Rheumatoid arthritis (RA) is another severe autoimmune disorder that impacts a significant percentage of the population. RA is a systemic disease characterized by chronic inflammation primarily of the synovial membrane lining of the joints, although the disease can effect a host of other tissues, such as the lung. This joint inflammation leads to chronic pain, loss of function, and ultimately to destruction of the joint. The presence of T-cells in the synovia, as well as other lines of evidence, indicate an autoimmune disease etiology. A number of autoantigen candidates for this disease have been tentatively identified, including type II collagen, human cartilage protein gp39 and gp130-RAPS. Existing treatment regimens for RA include anti-inflammatory drugs (both steroidal and non-steroidal), cytotoxic therapy (e.g., cyclosporine A, methotrexate and leflunomide), and biological immune modulators such as interleukins-1 and -2 receptor antagonists, anti-tumor necrosis factor alpha (TNFα) monoclonal antibodies, and TNFα receptor-IgG1 fusion proteins, frequently in conjunction with methotrexate (Davidson and Diamond, N. Engl. J. Med., 345(5):340-350 [2001]). However, these biological modifier therapies are suboptimal for a variety of reasons, notably do to their limited effectiveness and toxicity such as the systemic cytokine release syndrome seen with administration of a number of cytokines (e.g., IL-2), or the recently recognized increased risk of infection with anti-TNFα treatments.
In T-cells isolated from patients with this disease, it has been observed that some T-cell receptor (TCR) β-subunit variable domains (Vβ) appear to be preferentially utilized compared to disease-free subjects. It is suggested that peptides corresponding to these preferentially utilized TCR Vβ domains can be used in peptide vaccination therapy, where vaccination will result in disease-specific anti-TCR antibodies, and hopefully alleviate the disease (Bridges and Moreland, Rheum. Dis. Clin. North Am., 24(3):641-650 [1998]; and Gold et al., Crit. Rev. Immunol., 17 (5-6):507-510 [1997]). This therapy is under development (Moreland et al., J. Rheumatol., 23(8):1353-1362 [1996]; and Moreland et al., Arthritis Rheum., 41(11):1919-1929 [1998]), but has proven to be problematic due to the lack of consistency in TCR use in humans as opposed to what was observed in experimental animals.
A proposed alternative to antibody-based therapies for rheumatoid arthritis and other autoimmune diseases are therapies that incorporate major histocompatibility complex class II proteins (MHC II) covalently coupled with autoreactive peptides (Sharma et al., Proc. Natl. Acad. Sci. USA 88:11465-11469 [1991]; and Spack et al., Autoimmunity 8:787-807 [1995]). A variation of this MHC-based therapy incorporates covalently coupled Fcγ domains for the purpose of producing dimeric MHC/antigen fusion polypeptides (Casares et al., Protein Eng., 10(11):1295-1301 [1997]; and Casares et al., J. Exp. Med., 190(4):543-553 [1999]). However, these approaches based on artificial antigen presentation in the context of an MHC II fusion protein are unlikely to be widely applicable in human systems, as the MHC loci in humans are multiallelic (i.e., there exist many haplotype variations).
Another autoimmune disorder impacting a significant portion of the population is multiple sclerosis (MS), which afflicts approximately 250,000 people in the United States alone. MS manifests mainly in adults, and displays a wide array of neurological-related symptoms that vary unpredictably over decades, and may relapse, progress, or undergo spontaneous remission. No therapies currently exist that can arrest the progression of the primary neurologic disability caused by MS. Current therapies favor the use of glucocorticosteroids, but unfortunately corticosteroid therapies are not believed to alter the long-term course of the disease. Furthermore, corticosteroids have many side effects, including increased risk of infection, osteoporosis, gastric bleeding, cataracts and hypertension. Immunosuppressants are sometimes tried in progressive MS, but with equivocal results. Biological immune modulators, such as interferons α and β1a, and copolymer I, have also been tried in an attempt to downregulate the immune response and control the progression of the disease. Administration of interferon-β to suppress general immune function in patients with multiple sclerosis has had some limited success (Rose and MacKay (Eds.), The Autoimmune Diseases, Third Edition, Academic Press, p. 572-578 [1998]; Davidson and Diamond, N. Engl. J. Med., 345(5):340-350 [2001]). However, these biological modifiers have the drawback of limited efficacy and systemic side effects of fever and flu-like reactions.
The varied neurological-related symptoms of MS are the result of degeneration of the myelin sheath surrounding neurons within the central nervous system (CNS), as well as loss of cells that deposit and support the myelin sheaths, i.e., the oligodendrocytes, with ensuing damage to the underlying axons. T-cells isolated from patients with MS respond to myelin-basic-protein (MBP) by proliferating and secreting proinflammatory cytokines, indicating that endogenous MBP is at least one of the autoantigens being recognized in patients with the disease. The immunodominant epitope on the MBP protein has been shown to reside within the MBP83-99 region. As is the case in many autoimmune diseases, at least one other autoantibody has been implicated as the causative agent in patients with multiple sclerosis. This autoantibody appears to be specific for myelin oligodendrocyte glycoprotein (MOG), with a dominant epitope at MOG92-106.
Peptide immunotherapies using the MBP epitope to treat MS have been tested in animal models and in humans (e.g., Weiner et al., Science 259(5099):1321-1324 [1993]; Warren et al., Jour. Neuro. Sci., 152:31-38 [1997]; Goodkin et al., Neurology 54:1414-1420 [2000]; Kappos et al., Nat. Med., 6(10):1176-1182 [2000]; Bielekova et al., Nat. Med., 6(10):1167-1175 [2000]; and Steinman and Conlon, Jour. Clin. Immunol., 21(2):93-98 [2001]). Unfortunately, those studies using human subjects have been disappointing, with significant toxicity and hypersensitivity reactions reported. Furthermore, multiple sclerosis autoantigen immunotherapy may actually exacerbate the disease in some cases (McFarland, Science 274(5295):2037 [1996]; and Genain et al., Science 274:2054-2057 [1996]).
What is needed are improved and/or novel therapeutic strategies for the treatment of immune diseases resulting from inappropriate or unwanted immune response. What are needed are methods for the treatment of autoimmune diseases that are widely applicable to many autoimmune diseases, do not have the toxic effects of broad immunosuppressant drugs, and act in an autoantigen-restricted manner, thereby preserving a patient's immune function. Accordingly, there is a need for improved methods for peptide tolerance immunotherapies that have reduced risk of hypersensitivity reactions, and most notably, anaphylactic responses. Similarly, there is a need for compositions and methods that permit higher dosages of traditional peptide tolerance therapies, without the risk of inducing hypersensitivity responses.
The object of this invention is to provide novel and/or improved therapeutic strategies for the treatment of immune diseases resulting from inappropriate or unwanted immune response. Allergic diseases and autoimmune diseases are two such types of diseases which can be treated with the compositions and methods provided by the present invention. Allergic diseases which may be treated using the invention include, but are not limited to, for example, atopic allergies such as asthma, allergic rhinitis, atopic dermatitis, severe food allergies, some forms of chronic urticaria and angioedema, as well as the serious physiological condition of anaphylactic shock (i.e., anaphylactic hypersensitivity) resulting from, for example, bee stings or penicillin allergy. Autoimmune diseases which can be treated using the present invention include, but are not limited to, autoimmune diabetes, rheumatoid arthritis, and multiple sclerosis, for example.
The methods for treating allergic and autoimmune diseases provided by the invention can also be used in conjunction with traditional peptide immunotherapies, where the fusion molecules described herein are administered before, during or after the peptide immunotherapy, and find particular use in preventing the anaphylactic reactions associated with traditional immunotherapies.